Type 1 (T1D) diabetes results from the immune mediated loss of ? cell mass and function. With a reduced proliferation, and an increase immune mediated ? cell apoptosis, insulin producing cells become insufficient to adequately regulate body glycemia. The historical dogma for which soon after T1D diagnosis ? cell were fully and permanently lost has been challenged by recent studies revealing that even patients with long-standing diabetes residual ? cells are retained as demonstrated by the presence of insulin positive islets in the pancreas and by increase production of endogenous insulin after mixed-meal tolerance test. T1 diabetes can thus been seen as a chronic disease in which the balance exist between ? cells autoimmune destruction, regeneration, and resistance to apoptosis. Clinically this balance is obviously tilted toward the progressive loss of ? cell mass, however, it might be theoretically possible to normalize ? cell homeostasis by reducing loss, recovering function, and enhancing regeneration of remnant ? cells. Recent advancements in the understanding ? cell biology and in the field of RNA therapeutics offer an unprecedented opportunity for a targeted manipulation selectively in ? cells of those genes that control cell proliferation, apoptosis and resistance to autoimmunity. We propose that RNA aptamers specific for islet cells might be the tool for the specific delivery of therapeutic RNA able to positively and negatively modulate gene expression in endogenous and transplanted ? cells. RNA aptamers are small, RNAse resistant, non-immunogenic oligonucleotide that can penetrate deeply into the tissue and recognize their target in virtue of their three dimensional structure with high affinity and specificity. These synthetic antibodies are chemically synthetized, can be easily conjugated with small interference or small activating RNAs (siRNA or saRNA) and can be selected to penetrate into the cytoplasm upon target binding. We have recently identified by an unsupervised selection method, bioinformatics analysis and empirical validation, two monoclonal RNA aptamers able to recognized preferentially human ? cells in vivo. With the long term goal to beneficially modulate ? cell homeostasis and defense from auto-immunity in vivo, we decided to conjugate these aptamer with small RNA able to upregulate PDL1 and Xiap (to allow ? cell to fight back the immunologic attack and inhibit apoptosis respectively) and to down-regulate p57kip2 (to promote ? cell proliferation). Preliminary in vitro data using non-dissociated human islets demonstrated that the resulting therapeutic-RNA/islet-specific aptamer chimera effectively modulate the expression of the target genes. With this proposal we will test the hypothesis that aptamer-chimeras can be mediated in vivo gene modulation in human islet cells. This should allow to modify ? cell function and homeostasis by preventing their loss, by increasing their proliferation, and by providing protection from autoimmunity. This innovative approach may allow the development of novel therapeutic strategies for T1D based on the in vivo targeted modulation of ? cell genes.